For the past several years, the concept of metabolic syndrome has been expounded by WHO (the World Health Organization) as well as the National Cholesterol Education Program (NCEP) in the United States. The metabolic syndrome is the state in which various diseases causing arteriosclerosis, for example, visceral fat obesity, insulin resistance, diabetes, hyperlipemia, hypertension, etc. cluster together, so that angina pectoris, myocardial infarction or the like occurs easily. It is considered that the metabolic syndrome is ascribable to visceral adiposity and hypertrophic adipocytes.
The following two mechanisms have been revealed as how the visceral adiposity is associated with the development of diabetes, hyperlipemia, hypertension or the like. One is the mechanism in which a large amount of glyceride accumulated in visceral fat is decomposed in the fasting state, and a large amount of free fatty acid and glycerol, which are products of the decomposition, are released and flow in excess into the liver, leading to hyperlipemia, hyperglycemia and hyperinsulinism. The other is the mechanism in which the visceral adiposity causes abnormal adypocytokine secretion, which inhibits the secretion of adiponectin, for example, so that diabetes, arteriosclerosis or the like occurs (for example, see Non patent document 1). It has been revealed that the adiponectin activates a peroxisome proliferator-activated receptor (PPAR) α and AMP kinase so as to promote fatty acid burning or the like, thus decreasing the content of neutral fats in tissue and thereby, for example, relieving the insulin resistance or the like. Further, there has been a report that, besides the above, the adiponectin has antidiabetic, anti-arteriosclerotic, antihypertensive and anti-inflammatory effects.
On the other hand, PPARs, which are intranuclear receptors, are said to be associated with the relief of insulin resistance, hyperinsulinism, type 2 diabetes as well as obesity, hypertension, hyperlipemia and arteriosclerosis. PPARs are known to have three types, i.e., α, δ and γ, and several subtypes. PPARα is expressed mainly in the hepatic cells and also in other cells such as myocardial cells and gastrointestinal cells, and concerned with fatty acid oxidation, ketogenesis and apolipoprotein generation. Although PPARδ is not considered to have tissue specificity and is expressed throughout the body, it is expressed notably in large intestinal cancer cells. PPARγ can be classified into two subtypes, i.e., type γ1 and type γ2. The type γ1 is expressed in adipose tissues, immune system tissues, the adrenal gland and the small intestine, whereas the type γ2 is expressed specifically in adipocytes and plays an important role in differentiation induction of the adipocytes and fat synthesis.
The number of patients afflicted with the metabolic syndrome tends to increase mainly in developed countries. Accordingly, there is an urgent need for a metabolic syndrome relieving agent that has excellent safety and can be taken over a long term.
Non patent document 1: Yuji MATSUZAWA, “Concept of Metabolic Syndrome and Molecular Mechanism,” The Journal of Therapy, November 2004, Vol. 86, No. 11, pages 011-016.